Genetic Variant NM_001374504.1:c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA (chr22-37069345-C-CTGGGGTGGGGTGGGGTGGGGTGGGG) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001374504.1(TMPRSS6):c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA variant causes a splice acceptor, intron change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMPRSS6
NM_001374504.1 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.94

Publications

0 publications found

Variant links:

Genes affected

TMPRSS6 (HGNC:16517): (transmembrane serine protease 6) The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS6 Gene-Disease associations (from GenCC):

IRIDA syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

TMPRSS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11290992 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 0 (no position change), new splice context is: cccaccccaccccaccccAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMPRSS6	NM_001374504.1	MANE Select	c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	NP_001361433.1
TMPRSS6	NM_001289000.2		c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	NP_001275929.1
TMPRSS6	NM_001289001.2		c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	NP_001275930.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMPRSS6	ENST00000676104.1	MANE Select	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	ENSP00000501573.1
TMPRSS6	ENST00000406856.7	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	ENSP00000384964.1
TMPRSS6	ENST00000346753.9	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCA	splice_acceptor intron	N/A	ENSP00000334962.6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

90956

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000916

AC:

AN:

327528

Hom.:

Cov.:

AF XY:

0.00000588

AC XY:

AN XY:

170130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9810

American (AMR)

AF:

0.00

AC:

AN:

12212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8892

East Asian (EAS)

AF:

0.00

AC:

AN:

14618

South Asian (SAS)

AF:

0.00

AC:

AN:

26598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1618

European-Non Finnish (NFE)

AF:

0.0000139

AC:

AN:

215612

Other (OTH)

AF:

0.00

AC:

AN:

15184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

90956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42994

African (AFR)

AF:

0.00

AC:

AN:

26598

American (AMR)

AF:

0.00

AC:

AN:

7108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2228

East Asian (EAS)

AF:

0.00

AC:

AN:

3364

South Asian (SAS)

AF:

0.00

AC:

AN:

2042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42444

Other (OTH)

AF:

0.00

AC:

AN:

1136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over